Prepubertal Testicular Teratomas and Epidermoid Cysts

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1 ORIGINAL RESEARCH Prepubertal Testicular Teratomas and Epidermoid Cysts Comparison of Clinical and Sonographic Features Min-Yung Chang, MD, Hyun Joo Shin, MD, Hyun Gi Kim, MD, Myung-Joon Kim, MD, PhD, Mi-Jung Lee, MD, PhD Received September 17, 2014, from the Department of Radiology and Research Institute of Radiological Science, Severance Children s Hospital, Yonsei University College of Medicine, Seoul, Korea. Revision requested October 21, Revised manuscript accepted for publication December 28, Address correspondence to Mi-Jung Lee, MD, PhD, Department of Radiology and Research Institute of Radiological Science, Severance Children s Hospital, Yonsei University College of Medicine, 50-1Yonsei-ro, Seodaemun-gu, Seoul , Korea. mjl1213@yuhs.ac Abbreviations AFP, a-fetoprotein; AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic doi: /ultra Objectives To evaluate clinical and sonographic features of testicular teratomas and epidermoid cysts in children and to assess differential points of immature teratomas from benign counterparts. Methods We retrospectively reviewed testicular teratomas and epidermoid cysts in children. Age at surgery, α-fetoprotein (AFP) level, and sonographic findings, including components (mainly cystic, mainly solid, or mixed), presence of calcification, and size, were reviewed. Results Nineteen cases were included, with 10 mature teratomas, 3 immature teratomas, and 6 epidermoid cysts. On sonography, most of the teratomas (n = 9) had mixed components, with 2 mainly cystic and 2 mainly solid lesions. The 2 mainly cystic tera - tomas underwent follow-up sonography and showed component changes to mainly solid. Compared to epidermoid cysts, teratomas were larger (P =.029) with less cystic components (P =.046). All 3 immature teratomas showed mixed components with calcification. In differentiating immature from benign teratomas, immature teratomas were larger (P =.047) in younger children (P =.008) with higher AFP levels (P =.023). The optimal cutoff values for diagnosing immature teratomas were 8 months of age, 23 ng/ml in AFP level, and 2.5 cm in size, with 100% sensitivity and 89.5% accuracy rates. However, sonographic features, including tumor components and presence of calcification, were not helpful for differentiating immature teratomas. Conclusions Testicular masses in children younger than 8 months with AFP levels higher than 23 ng/ml and size larger than 2.5 cm need to be considered for orchiectomy rather than testis-sparing tumorectomy because of the increased frequency of immature teratomas versus mature teratomas or epidermoid cysts. Key Words child; epidermoid cyst; genitourinary ultrasound; pediatric ultrasound; sonography; teratoma; testis P repubertal testicular and paratesticular tumors are rare and constitute 1% to 2% of all pediatric solid neoplasms. 1 The tumors differ from postpubertal testicular tumors in that they show a more benign course. 2 Although seminoma is the most prevalent tumor type in adults, it is rare in children. Teratomas are predominant even though there is controversy about the most common type of prepubertal testicular tumor. 3,4 Most patients present with scrotal enlargement. With physical examination, patients suspected to have a testicular tumor undergo sonography for the first imaging study. When a testicular mass is identified on sonography, testis-sparing surgery with tumorectomy 2015 by the American Institute of Ultrasound in Medicine J Ultrasound Med 2015; 34:

2 can be performed for benign tumors as a treatment of choice for both successful tumor control and testicular preservation. 5 Radical orchiectomy, however, is needed for malignant tumors. Therefore, precise preoperative diagnosis of malignancy is important for proper treatment planning. Nevertheless, there are limited studies about sonographic findings for prepubertal testicular tumors, and the diagnosis mostly relies on that of the adult counterparts. In a study performed in adults, 6 there were considerable similarities in sonographic appearances between testicular epidermoid cysts and teratomas. However, to date, only a few studies have examined sonographic findings limited to mature testicular teratomas in children. 4,7 There are currently no studies that have compared sonographic findings between mature teratomas, immature teratomas, and epidermoid cysts in children. Generally, immature teratomas are benign; however, metastatic spreading can occur, and careful examination is needed to exclude any focal areas of a yolk sac tumor. 8 Thus, the objective of our study was to review clinical and sonographic characteristics of testicular epidermoid cysts, mature teratomas, and immature teratomas. Materials and Methods The Institutional Review Board at our hospital approved this retrospective study and waived the requirement of informed consent. Two radiologists retrospectively reviewed the medical records of children younger than 18 years at the time of surgery with pathologically confirmed testicular teratomas or epidermoid cysts from January 2006 to March 2014 at our hospital. Age at the time of surgery, preoperative a-fetoprotein (AFP) levels, sonographic images and findings, and pathologic diagnoses were reviewed. All sonographic examinations were performed with high frequency linear transducers. We used a single ultrasound machine (iu22; Philips Healthcare, Best, the Netherlands) with a 5 12-MHz linear transducer. We also reviewed sonograms from outside the hospital brought by patients, if available. The sonographic characteristics that were reviewed included tumor components, presence of calcification, and tumor size. Tumor components were classified into 3 categories: mainly cystic when there was more than an 80% cystic portion, mainly solid when there was more than an 80% solid portion, and mixed when the lesion was neither mainly cystic nor mainly solid. Calcification was defined as a hyperechoic spot with or without discernible posterior acoustic shadowing because, in cases with microcalcification, posterior acoustic shadowing may not appear. Tumor size was measured as the longest diameter of the tumor in any plane. Doppler sonographic findings in the solid portion were also reviewed and categorized as increased vascular flow or not. Preoperative follow-up sonographic examinations, if present, were also reviewed. However, only initial findings were used for statistical analyses. Statistical analyses were performed with SPSS version 20.0 software (IBM Corporation, Armonk, NY). We evaluated differential points between teratomas (teratoma group) and epidermoid cysts (epidermoid cyst group) and between immature teratomas (immature group) and benign lesions, including mature teratomas and epidermoid cysts (benign group), in children. A Mann-Whitney U test was performed to compare patient age, preoperative AFP level, and tumor size. A Fisher exact test was performed to compare tumor components, presence of calcification, and vascular flow on Doppler sonography. To obtain the optimal cutoff values for the continuous variables, a receiver operating characteristic (ROC) analysis was performed. Using the cutoff values, sensitivity, specificity, and accuracy were also calculated. P <.05 was considered statistically significant. Results Twenty-one testicular tumors from 20 children underwent surgery during the study period. Among these, 2 patients underwent tumorectomy without preoperative imaging studies because of a testicular tumor that was incidentally identified during orchiopexy for cryptorchidism in the inguinal area without a palpable mass on physical examination by a pediatric urologist. Therefore, a total of 19 testicular tumors from 18 children with preoperative sonographic evaluations were included in this study. Fourteen children had sonograms from outside the hospital. The number of sonograms was 3 to 23, with the mean of 9. The pathologic diagnoses were mature teratomas in 10 cases, immature teratomas in 3, and epidermoid cysts in 6. Two immature teratomas were grade 1 (probably benign), and 1 was grade 3 (frankly malignant). 9 Age at the time of surgery ranged from 1 to 64 months. One patient had bilateral testicular lesions in which one testis contained a mature teratoma and the other had an epidermoid cyst (Figure 1). Table 1 summarizes the clinical and sonographic features of the teratoma and epidermoid cyst groups. The median age at the time of surgery was younger in the teratoma group than in the epidermoid cyst group, without a significant difference. Preoperative AFP levels were also not significantly different between the groups. However, lesion size was larger in the teratoma group than in the epidermoid cyst group. In the ROC analysis, the area under 1746 J Ultrasound Med 2015; 34:

the curve (AUC) for tumor size was 0.821 (SE, 0.098; 95% confidence interval [CI], 0.579 0.954; P =.028), and the optimal size cutoff value was 1.25 cm, with 84.6% sensitivity, 66.

However, most of the epidermoid cysts (n = 4) presented as mainly cystic lesions, with 1 mixed and 1 mainly solid lesion.

Intratumoral calcification on sonography was detected in a greater proportion of cases in the teratoma group than in the epidermoid cyst group, without a significant difference.

3 the curve (AUC) for tumor size was (SE, 0.098; 95% confidence interval [CI], ; P =.028), and the optimal size cutoff value was 1.25 cm, with 84.6% sensitivity, 66.7% specificity, and 78.9% accuracy. Considering the sonographic features, the teratomas had various components, from mainly cystic (n = 2) and mixed (n = 9) to mainly solid (n = 2). However, most of the epidermoid cysts (n = 4) presented as mainly cystic lesions, with 1 mixed and 1 mainly solid lesion. The sonographic tumor components were significantly different between the groups in that mainly cystic lesions favored epidermoid cysts (Figure 1). Intratumoral calcification on sonography was detected in a greater proportion of cases in the teratoma group than in the epidermoid cyst group, without a significant difference. None of the 19 tumors showed an onion ring appearance in this study. On Doppler sonography, none of the epidermoid cysts showed increased vascularity, compared to 5 cases in the teratoma group. Preoperative follow-up sonographic examinations were performed in 3 patients who had simple cystic lesions in the testes at the first sonographic examinations. One patient had a 3-month follow-up sonographic study; the imaging did not show an interval change, and the mass was confirmed to be an epidermoid cyst. The other 2 patients were evaluated with 1- and 2-year follow-up sonography and showed component changes from mainly cystic to mainly solid (Figure 2); however, the tumor sizes were decreased. Tumorectomy was performed, and both cases were confirmed to be mature teratomas. Table 2 shows a comparison between the immature and benign groups for clinical and sonographic features. The ages of the patients at the time of surgery were younger in the immature group. Preoperative AFP levels were higher in the immature group than the benign group. Table 1. Clinical and Sonographic Features in the Teratoma and Epidermoid Cyst Groups Epidermoid Teratoma Cyst Characteristic (n = 13) (n = 6) P Age, mo 13 (1 57) 24 (3 64).368 AFP, ng/ml 3.7 ( ) 3.3 ( ).765 Size, cm 2.0 ( ) 0.9 ( ).029 Mainly cystic component 2 (15) 4 (67).046 Presence of calcification 10 (77) 2 (33).129 Increased vascular flow on Doppler sonography 5 (38) 0 (0).128 Data are presented as median (range) and number (percent) where applicable. Figure 1. Left testicular mature teratoma and incidentally found right testicular epidermoid cyst in a 13-month-old boy. A, Left scrotal sonography shows a 1.8-cm ovoid mixed solid and cystic mass with heterogeneous echogenicity and internal calcifications in the left testis, which was confirmed as a mature teratoma. B, On color Doppler imaging, the left testicular mass shows increased vascularity. C, Right scrotal sonography shows a 1.2-cm cystic mass with a peripheral hyperechoic rim in the left testis, which was pathologically diagnosed as an epidermoid cyst. The preoperative AFP level was 3.74 ng/ml (normal range, 0 9 ng/ml). J Ultrasound Med 2015; 34:

Tumor sizes were also significantly different between the groups. All 3 immature teratomas appeared as mixedcomponent masses with calcification (Figure 3).

However, tumor components, presence of calcification, and vascular flow on Doppler sonography were not significantly different between the groups.

4 Tumor sizes were also significantly different between the groups. All 3 immature teratomas appeared as mixedcomponent masses with calcification (Figure 3). Only 1 of 3 immature teratomas showed increased vascular flow on Doppler sonography. However, tumor components, presence of calcification, and vascular flow on Doppler sonography were not significantly different between the groups. When these groups were compared, age, AFP level, and tumor size were found to be meaningful. The ROC analysis is shown in Figure 4. The optimal age cutoff value was 8 months, with 100% sensitivity, 87.5% specificity, and 89.5% accuracy. The optimal AFP level cutoff value was 23 ng/ml, with 100% sensitivity, 87.5% specificity, and 89.5% accuracy. The optimal tumor size cutoff value was 2.5 cm, with 100% sensitivity, 81.3% specificity, and 89.5% accuracy. Figure 2. Left testicular mature teratoma in a 27-month-old boy. A, Initial scrotal sonography, which was performed 2 years previously at an outside hospital, shows a 1.5-cm cystic mass without a visible solid portion in the left testis. B, Follow-up sonography shows that the testicular lesion changed to a mainly solid component. The tumor size decreased to 0.4 cm. There was no internal calcification. This lesion was confirmed as a mature teratoma by surgical pathologic examination. The preoperative AFP level was 2.05 ng/ml. Discussion Our study demonstrated that prepubertal testicular teratomas had variable sonographic features and that the features could change over time. However, younger age, higher AFP level, and larger tumor size were more frequently associated with immature teratomas than mature teratomas or epidermoid cysts. With regard to tumor components, our cases showed components that varied from cystic to solid. This result supportsthe findings of a previous study that had a limited number of prepubertal cases of mature testicular teratomas. 4,7 Moreover, the 2 initial mainly cystic mature teratomas showed changes to mainly solid components on follow-up sonography. Garrett et al 10 reviewed testicular cystic lesions in children and included differential diagnoses of epidermoid cysts, dermoid cysts, prepubertal teratomas, juvenile granulosa cell tumors, cystic dysplasia of the rete testis, testicular cystic lymphangiomas, simple cysts, and cystic degeneration after torsion. However, the study that reported component changes in testicular teratomas was limited. Hoag et al 11 reviewed cystic intratesticular lesions in children and mentioned that 3 of 7 lesions showed gradual decreases in size, including 1 complete resolution. The pathologic results for the 2 lesions that decreased in size without resolution were an epidermoid cyst in 1 and a mature teratoma with an adjacent intratubular germ cell tumor in the other. They also reported 1 epidermoid cyst that decreased in size at first but increased in size later. Another case report discussed a simple cystic teratoma in a 5-month-old boy. 12 In that case, follow-up sonography was performed after 1 month, and there was no indication of an interval change. Therefore, when there is a simple cystic lesion in the pediatric testis, a testicular teratoma cannot be excluded and is more likely if component changes are identified on follow-up sonography. Table 2. Clinical and Sonographic Features in the Immature and Benign Groups Immature Benign Characteristic (n = 3) (n = 16) P Age, mo 3.0 (1 8) 13.5 (3 64).008 AFP, ng/ml 47.5 ( ) 3.1 ( ).023 Size, cm 2.8 ( ) 1.6 ( ).047 Mixed component 3 (100) 7 (44).530 Presence of calcification 3 (100) 9 (56).263 Increased vascular flow on Doppler sonography 1 (33) 4 (25) >.999 Data are presented as median (range) and number (percent) where applicable J Ultrasound Med 2015; 34:

B, On color Doppler imaging, the mass shows minimal vascularity. The preoperative AFP level was elevated to 784.94 ng/ml. Figure 4.

5 Figure 3. Right testicular immature teratoma (grade 3) in a 3-month-old boy. A, Preoperative scrotal sonography shows a 4.9-cm mixed solid and cystic mass that replaced the right testis, which was pathologically diagnosed as an immature teratoma. B, On color Doppler imaging, the mass shows minimal vascularity. The preoperative AFP level was elevated to ng/ml. Figure 4. Receiver operating characteristic curves for obtaining an optimal cutoff value for diagnosis of immature teratomas. A, The AUC for age was (95% CI, ; P =.014). B, The AUC for preoperative AFP level was (95% CI, ; P = 0.025). C, The AUC for tumor size was (95% CI, ; P =.044). J Ultrasound Med 2015; 34:

6 In our study, the sonographic findings indicated that epidermoid cysts were statistically more frequently associated with a smaller tumor size (P =.029) and mainly cystic components (P =.046). Teratomas are complex tumors derived from all 3 germ layers, including the endoderm, mesoderm, and ectoderm. The current hypothesis contends that even though histogenesis of epidermoid cysts is controversial, monodermal teratomas can occur without endodermal or mesodermal components. 10 This hypothesis could explain the considerable similarities between epidermoid cysts and teratomas when assessed with sonography. An onion ring appearance is a characteristic sonographic finding of epidermoid cysts and was first described by Malvica. 13 In this finding, concentric rings of alternating hypoechogenicity and hyperechogenicity correlate with the alternating layers of keratinizing squamous epithelium, compacted keratin, and desquamated epithelium. 14 Maizlin et al 6 demonstrated the considerable overlapping of the sonographic appearances of teratomas and epidermoid cysts in an adult study. They reported that not only 3 of 5 epidermoid cysts but also all 3 teratomas showed the onion ring appearance. 6 However, none of the 19 tumors in our study showed this finding, which could have been attributable to the small number of patients in our study. To our knowledge, no previous study has evaluated sonographic features of pediatric immature testicular teratomas. Teratomas commonly are classified according to the Gonzalez-Crussi grading system: 0, mature, benign; 1, immature, probably benign; 2, immature, possibly malignant (cancerous); and 3, frankly malignant. 9 We had 3 immature teratomas, including only 1 that was grade 3. However, all immature teratomas with or without malignant elements need to undergo complete surgical excision. 15 In addition, all 3 of the immature teratomas in this study showed mixed components with calcification. However, these findings were not statistically significant for differentiating this group from the benign group. Clinical data, including younger age, higher AFP level, and larger tumor size, however, were important for differentiating immature teratomas from benign counterparts. According to these findings, we found the optimal cutoff values for the diagnosisof immature teratomas to be 8 months of age, 23 ng/ml in AFP level, and 2.5 cm in size. Wang et al 2 reviewed 60 primary prepubertal testicular tumors over a 10-year period and found that 27 (45%) were mature teratomas, and 5 (13%) were immature teratomas. The median ages at presentation were 9 months in children with mature teratomas and 4 months in children with immature teratomas, and these results were comparable with our study. They also reported that 2 of 5 children with immature teratomas had abnormal AFP levels, although the mean value or cutoff value was not suggested. Even though our results were obtained by assessing only 3 immature teratomas among 19 testicular masses, the cutoff values showed 100% sensitivity and 89.5% accuracy. Because the normal AFP level in infants can be higher than in adults until 8 months of age, 16 the cutoff value of 23 ng/ml can be within normal limits in young infants. Therefore, more concern is warranted for testicular masses that are larger than 2.5 cm in infants younger than 8 months. Ahmed et al 8 also commented that testicular-sparing surgery should be used in any patient with a testicular tumor in which the normal testicular tissue could be salvaged, based on sonography, with a normal AFP level or, if the child is younger than 12 months, with an AFP level that is high but less than 100 ng/ml. However, sonography can underestimate the amount of normal residual parenchyma because of tumor compression, which affects determination of salvageable testicular tissue. 17 Therefore, the estimated normal residual parenchyma on preoperative sonography should not be used as a factor for patients who want to opt for testicular-sparing surgery. Our study had several limitations. First, the study population was small, even though prepubertal testicular tumors are rare. There were only 3 cases of immature teratomas, which was too small a number to perform an ROC analysis. The suggested cutoff AFP level can be within normal limits in young infants. Additional studies with larger numbers of patients are needed to verify our cutoff value for differentiating immature teratomas from benign tumors. The second limitation was that this study was retrospective. The absence of calcification may not have been reliable, even though we reviewed not only images but also imaging reports. Additional prospective studies with slide-by-slide pathologic correlation are needed to identify a unique feature of immature teratomas for imaging studies. In conclusion, sonographic findings of testicular teratomas can vary from cystic to solid and even can change during follow-up. Consideration of orchiectomy rather than testis-sparing tumorectomy is needed for tumors larger than 2.5 cm in children younger than 8 months because of the increased possibility of immature teratomas. References 1. Canali R, Angelini L, Castagnetti M, Zhapa E, Rigamonti W. Scrotal dermoid extending to the posterior urethra through a corpus cavernosum in a child. 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7 2. Wang X, Xu S, Tang D, Li M, Wu D, Huang Y. Prepubertal testicular and paratesticular tumors in China: a single-center experience over a 10-year period. J Pediatr Surg 2012; 47: Agarwal PK, Palmer JS. Testicular and paratesticular neoplasms in prepubertal males. J Urol 2006; 176: Epifanio M, Baldissera M, Esteban FG, Baldisserotto M. Mature testicular teratoma in children: multifaceted tumors on ultrasound. Urology2014; 83: Bujons A, Sfulcini JC, Pascual M, Feu OA, Garat JM, Villavicencio H. Prepubertal testicular tumours and efficacy of testicular preserving surgery. BJU Int 2011; 107: Maizlin ZV, Belenky A, Baniel J, Gottlieb P, Sandbank J, Strauss S. Epidermoid cyst and teratoma of the testis: sonographic and histologic similarities. J Ultrasound Med 2005; 24: Liu P, Phillips MJ, Edwards VD, Ein S, Daneman A. Sonographic findings of testicular teratoma with pathologic correlation. Pediatr Radiol 1992; 22: Ahmed HU, Arya M, Muneer A, Mushtaq I, Sebire NJ. Testicular and paratesticular tumours in the prepubertal population. Lancet Oncol2010; 11: Gonzalez-Crussi F. Extragonadal Teratomas. Washington, DC: Armed Forces Institute of Pathology; Garrett JE, Cartwright PC, Snow BW, Coffin CM. Cystic testicular lesions in the pediatric population. J Urol 2000; 163: Hoag NA, Afshar K, Youssef D, Masterson JS, Murphy J, Macneily AE. Cystic intratesticular lesions in pediatric patients. J Pediatr Surg 2013; 48: Di Renzo D, Persico A, Sindici G, Lelli Chiesa P. Testicular teratoma, mimicking a simple testicular cyst, in an infant. Urology 2013; 82: Malvica RP. Epidermoid cyst of the testicle: an unusual sonographic finding. AJR Am J Roentgenol 1993; 160: Loya AG, Said JW, Grant EG. Epidermoid cyst of the testis: radiologicpathologic correlation. Radiographics 2004; 24(suppl 1):S243 S Marina NM, Cushing B, Giller R, et al. Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: a Pediatric Oncology Group/Children's Cancer Group intergroup study. J Clin Oncol 1999; 17: Wu JT, Book L, Sudar K. Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981; 15: Patel AS, Coley BD, Jayanthi VR. Ultrasonography underestimates the volume of normal parenchyma in benign testicular masses. J Urol 2007; 178: J Ultrasound Med 2015; 34:

Prepubertal Testicular Tumors in Korea: A Single Surgeon s Experience of More Than 20 Years

www.kjurology.org http://dx.doi.org/10.4111/kju.2013.54.6.399 Pediatric/Reconstructive Urology Prepubertal Testicular Tumors in Korea: A Single Surgeon s Experience of More Than 20 Years Kyungdon Baik,